Vaccination is one of the most successful medical practices since its invention 200 years ago, and has been successful in eradicating many severe infectious diseases (Plotkin, 2005; Mortellaro et al., 2011). Although very successful, the current state of vaccine development is not adequate to meet some emerging, re- emerging or persistent challenges. Infectious diseases are still responsible for one-fifth of all deaths worldwide, killing at least 11 million people every year (Kieny et al., 2005). Conventional vaccinology has failed in fighting many pathogens due to either high antigen variability or poor understanding of protection mechanisms. Rapid development of new vaccines against the persistent or new diseases is an urgent priority. While the conventional empirical approach has been necessary and may have paved the way to future success, it is vital to have new approaches that make full use of ever increasing immunological knowledge. To this end, the recent development of vaccines to combat cancer and vaccine-resistant infectious diseases has relied heavily on structurally defined subunit antigen constructs. Although there are many advantages of these vaccine candidates, the refined antigens are often less immunogenic, which necessitates the use of adjuvants. Adjuvants are the substances applied to enhance the ability of a vaccine to elicit strong and durable immune responses to a co-administered antigen (Kensil et al., 2004; Leroux-Roels, 2010; Brunner et al., 2010). They play crucial roles in vaccine development. One promising and unique adjuvant is QS-21, a saponin natural product that has been evaluated in many cancer and infectious disease vaccine clinical trials. It stimulates both Th1 and Th2 type responses, which are extremely important for the development of subunit vaccines against cancers and intracellular pathogens (e.g. HIV, TB and malaria) when a sufficiently potent cytotoxic T lymphocyte (CTL) response to purified antigens without toxicity issues is desired (Kensil et al., 2004; 2006). However, the natural saponin QS-21 has inherent drawbacks (e.g. its scarcity, difficulty and low-yielding in purification, chemical instability, an dose-limiting toxicity) which prevent it from wide use, especially in the production of reliable human vaccines other than for life-threatening diseases, such as HIV infection or cancer. The limitation of QS-21 highlights the need for new adjuvants with improved properties. Structural modification of QS-21 is an attractive and feasible method to address the need. Specific aim: To synthesize QS-21-based new adjuvants and obtain their preliminary adjuvanticity and toxicity data. PUBLIC HEALTH RELEVANCE: This project is to design and synthesize structurally defined and chemically stable new adjuvants, substances that can enhance the ability of a vaccine to elicit strong and durable immune responses. It is a crucial step toward developing new vaccines against persistent, emerging and/or re-emerging infectious diseases, and various cancers.